Microbial Stimulation by Mycoplasma fermentans Synergistically Amplifies IL-6 Release by Human Lung Fibroblasts in Response to Residual Oil Fly Ash (ROFA) and Nickel

Gao, Fei; Barchowsky, Aaron; Nemec, Antonia A.; Fabisiak, James P.

doi:10.1093/toxsci/kfh205

Cited by 25 publications

(30 citation statements)

References 58 publications

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“…Thus the most significant effect of mycoplasma in vivo may be fully realized only in the presence of other injurious or stressful stimuli. We have recently reported similar synergistic interactions between M. fermentans and metal-containing atmospheric particulate matter (17). It should be noted that not all HLF-derived cytokines were equally potentiated by M. fermentans.…”

Section: Discussionsupporting

confidence: 57%

Mycoplasma fermentansand TNF-β interact to amplify immune-modulating cytokines in human lung fibroblasts

Fabisiak

Gao²,

Thomson³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Mycoplasma can establish latent infections and are associated with arthritis, leukemia, and chronic lung disease. We developed an experimental model in which lung cells are deliberately infected with Mycoplasma fermentans. Human lung fibroblasts (HLF) were exposed to live M. fermentans and immune-modulating cytokine release was assessed with and without known inducers of cytokine production. M. fermentans increased IL-6, IL-8/CXCL8, MCP-1/CCL2, and Gro-α/CXCL1 production. M. fermentans interacted with TNF-β to release more IL-6, CXCL8, and CXCL1 than predicted by the responses to either stimulus alone. The effects of live infection were recapitulated by exposure to M. fermentans-derived macrophage-activating lipopeptide-2 (MALP-2), a Toll-like receptor-2-and receptor-6-specific ligand. The synergistic effect of combined stimuli was more pronounced with prolonged incubations. Preexposure to TNF-β sensitized the cells to subsequent MALP-2 challenge, but preexposure to MALP-2 did not alter the IL-6 response to TNF-β. Exposure to M. fermentans or MALP-2 did not enhance nuclear localization, DNA binding, or transcriptional activity of NF-κB and did not modulate early NF-κB activation in response to TNF-β. Application of specific inhibitors of various MAPKs suggested that p38 and JNK/stress-activated protein kinase were involved in early IL-6 release after exposure to TNF-β and M. fermentans, respectively. The combined response to M. fermentans and TNF-β, however, was uniquely sensitive to delayed application of SP-600125, suggesting that JNK/stress-activated protein kinase contributes to the amplification of IL-6 release. Thus M. fermentans interacts with stimuli such as TNF-β to amplify lung cell production of immune-modulating cytokines. The mechanisms accounting for this interaction can now be dissected with the use of this in vitro model. NIH Public Access Author ManuscriptAm J Physiol Lung Cell Mol Physiol. Author manuscript; available in PMC 2010 July 6. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript MYCOPLASMA (class Mollicute) are a class of microorganisms that need to be considered as a potential factor in the genesis of chronic inflammatory disease. These ubiquitous cell wall-free bacteria represent the simplest known self-replicating organisms and have adapted to a strict commensal/parasitic lifestyle in an intimate relationship with a variety of animal and human hosts. M. pneumoniae was identified as a causative agent for human tracheobronchitis and atypical pneumonia in 1962 (9); however, this and other species are now reemerging in their importance as covert and chronic infectious agents with potential to act as cofactors in the progression of chronic inflammatory disease (5,7). It was recently shown that M. pneumoniae and other mollicute species could be detected in the airways of subjects in the absence of symptoms of acute infection and that the incidence was greater in individuals with asthma (23).M. fermentans has been previously isolated from the human genitour...

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Section: Discussionsupporting

confidence: 57%

Mycoplasma fermentansand TNF-β interact to amplify immune-modulating cytokines in human lung fibroblasts

Fabisiak

Gao²,

Thomson³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Ni is a major component of ambient air particulate matter (1,35) that is associated with inappropriate immune responses (35,36), airway hyperresponsiveness (7,37), and increased cardiopulmonary disease (1). Mechanisms of action for inhaled Ni that are independent of its antigenicity remain poorly defined.…”

Section: Discussionmentioning

confidence: 99%

Nickel Mobilizes Intracellular Zinc to Induce Metallothionein in Human Airway Epithelial Cells

Nemec

Leikauf²,

Pitt³

et al. 2009

Am J Respir Cell Mol Biol

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We recently reported that induction of metallothionein (MT) was critical in limiting nickel (Ni)-induced lung injury in intact mice. Nonetheless, the mechanism by which Ni induces MT expression is unclear. We hypothesized that the ability of Ni to mobilize zinc (Zn) may contribute to such regulation and therefore, we examined the mechanism for Ni-induced MT2A expression in human airway epithelial (BEAS-2B) cells. Ni induced MT2A transcript levels and protein expression by 4 hours. Ni also increased the activity of a metal response element (MRE) promoter luciferase reporter construct, suggesting that Ni induces MRE binding of the metal transcription factor (MTF-1). Exposure to Ni resulted in the nuclear translocation of MTF-1, and Ni failed to induce MT in mouse embryonic fibroblasts lacking MTF-1. As Zn is the only metal known to directly bind MTF-1, we then showed that Ni increased a labile pool of intracellular Zn in cells as revealed by fluorescence-activated cell sorter using the Zn-sensitive fluorophore, FluoZin-3. Ni-induced increases in MT2A mRNA and MRE-luciferase activity were sensitive to the Zn chelator, TPEN, supporting an important role for Zn in mediating the effect of Ni. Although neither the source of labile Zn nor the mechanism by which Ni liberates labile Zn was apparent, it was noteworthy that Ni increased intracellular reactive oxygen species (ROS). Although both N-acetyl cysteine (NAC) and ascorbic acid (AA) decreased Ni-induced increases in ROS, only NAC prevented Ni-induced increases in MT2A mRNA, suggesting a special role for interactions of Ni, thiols, and Zn release.

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“…This is further confirmed by investigations that attribute different levels of toxicity to particles from different sources (Laden et al, 2000; Mar et al, 2000; Zhou et al (2011)). Toxicological studies have demonstrated the toxic potential of many individual PM components including sulfate, zinc, nickel and lead (Chuang et al, 2007; Gao et al, 2004; Lippmann et al, 2006; O’Neill et al, 2005). …”

Section: Introductionmentioning

confidence: 99%

A framework to spatially cluster air pollution monitoring sites in US based on the PM2.5 composition

Austin¹,

Coull

Zanobetti³

et al. 2013

Environment International

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Background Heterogeneity in the response to PM2.5 is hypothesized to be related to differences in particle composition across monitoring sites which reflect differences in source types as well as climatic and topographic conditions impacting different geographic locations. Identifying spatial patterns in particle composition is a multivariate problem that requires novel methodologies. Objectives Use cluster analysis methods to identify spatial patterns in PM2.5 composition. Verify that the resulting clusters are distinct and informative. Methods 109 monitoring sites with 75% reported speciation data during the period 2003–2008 were selected. These sites were categorized based on their average PM2.5 composition over the study period using k-means cluster analysis. The obtained clusters were validated and characterized based on their physico-chemical characteristics, geographic locations, emissions profiles, population density and proximity to major emission sources. Results Overall 31 clusters were identified. These include 21 clusters with 2 or more sites which were further grouped into 4 main types using hierarchical clustering. The resulting groupings are chemically meaningful and represent broad differences in emissions. The remaining clusters, encompassing single sites, were characterized based on their particle composition and geographic location. Conclusions The framework presented here provides a novel tool which can be used to identify and further classify sites based on their PM2.5 composition. The solution presented is fairly robust and yielded groupings that were meaningful in the context of air-pollution research.

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Microbial Stimulation by Mycoplasma fermentans Synergistically Amplifies IL-6 Release by Human Lung Fibroblasts in Response to Residual Oil Fly Ash (ROFA) and Nickel

Cited by 25 publications

References 58 publications

Mycoplasma fermentansand TNF-β interact to amplify immune-modulating cytokines in human lung fibroblasts

Mycoplasma fermentansand TNF-β interact to amplify immune-modulating cytokines in human lung fibroblasts

Nickel Mobilizes Intracellular Zinc to Induce Metallothionein in Human Airway Epithelial Cells

A framework to spatially cluster air pollution monitoring sites in US based on the PM2.5 composition

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